Ticlopidine hydrochloride is disclosed in U.S. Pat. No. 4,591,592 as a platelet aggregation inhibitor, is marketed in the U.S. under the name Ticlid.RTM. by Roche Laboratories, and has the chemical name 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and the structure ##STR1##
Clopidogrel is a thieno-[3,2-c]pyridine derivative which has the chemical name methyl (4)-(S)-.alpha.-(o-chloro-phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-aceta te and the formula ##STR2##
including pharmaceutically acceptable acid addition salts thereof, preferably the hydrogen sulfate salt, and is disclosed in U.S. Pat. Nos. 4,529,596 to Aubert et al and U.S. Pat. No. 4,847,265 to Badorc et al as having blood platelet aggregation inhibiting activity and anti-thrombotic activity and thus useful in inhibiting or preventing arterial and venous thrombosis.
U.S. Pat. No. 5,576,328 to Herbert et al discloses that clopidogrel may be employed in secondary prevention of ischemic events such as myocardial infarction, unstable or stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis after PTCA, thrombotic stroke, transient ischemic attack, reversible ischemic neurological deficit, and intermittent claudication.
The above Aubert et al, Badorc et al and Herbert et al patents are incorporated herein by reference.
WO 97/29753 published Aug. 21, 1997, discloses a pharmaceutical composition containing clopidogrel and aspirin.
Bernhart et al in U.S. Pat. No. 5,270,317 disclose a series of N-substituted heterocyclic derivatives which possess angiotensin II antagonist activity. Bernhart et al disclose that such compounds can be used in the treatment of various cardiovascular complaints, especially hypertension, heart failure, and venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathy and various complaints of the central nervous system. It is also disclosed that such compound can be used in combination with other active agents such as tranquilizers, beta-blocking compounds, a calcium antagonist, or a diuretic.
Selective neutral endopeptidase inhibitors are taught by Delaney et al in U.S. Pat. Nos. 4,722,810 and 5,223,516 and the use of selective neutral endopeptidase inhibitors alone or in combination with angiotensin converting enzyme inhibitors to treat hypertension are disclosed by Delaney et al U.K. Patent Application 2,207,351 and by Haslanger et al in U.S. Pat. No. 4,749,688. The treatment of congestive heart failure by administration of a combination of a selective neutral endopeptidase inhibitor and an angiotensin converting enzyme inhibitor is disclosed by Seymour in U.S. Pat. No. 5,225,401.
Compounds possessing both neutral endopeptidase and angiotensin converting enzyme inhibition activity are disclosed by Flynn et al in U.S. Pat. No. 5,366,973, European Patent Application 481,522 and PCT Patent Applications WO 93/16103, and WO 94/10193, Warshawsky et al European Patent Applications 534,363, 534,396 and 534,492, Fournie-Zaluski European Patent Application 524,553, Barrish et al European Patent Application 599,444, Karanewsky European Patent Application 595,610, Robl et al, European Patent Application 629,627, Robl U.S. Pat. No. 5,362,727 and U.S. patent application Ser. No. 153,854 filed Nov. 18, 1993, now U.S. Pat. No. 5,525,723.